Cyclic nucleotide phosphodiesterase (hereinafter referred to as phosphodiesterase or PDE) is an enzyme that hydrolyses a phosphodiester bond in cyclic nucleotides such as cAMP (adenosine 3′,5′-cyclic monophosphate) or cGMP (guanosine 3′,5′-cyclic monophosphate), etc. as a substrate, to provide nucleotides such as 5′AMP (adenosine 5′-monophosphate) or 5′GMP (guanosine 5′-monophosphate), etc.
Cyclic nucleotides such as cAMP and cGMP are involved in the regulation of many functions within a living body as second messengers of intracellular signaling. Intracellular concentrations of cAMP and cGMP, which vary in response to extracellular signals, are regulated by a balance between enzymes involved in synthesis of cAMP and cGMP (adenylate cyclase and guanylate cyclase) and PDE involved in hydrolysis of such enzymes.
For PDE of mammals, many kinds of PDEs have been isolated and identified in mammals so far, and they have been classified into plural families in accordance with amino-acid sequence homology, biochemical properties, characterization by inhibitors and the like (Francis et al., Prog. Nucleic Acid Res., vol. 65, pp. 1-52, 2001).
Among such various families of PDEs of mammals, phosphodiesterase 10 (PDE10) [more specifically phosphodiesterase 10A (PDE10A)] recognizes both cAMP and cGMP as a substrate. It has been reported that PDE10 has a greater affinity for cAMP. Further, cDNAs of human, mouse and rat PDE10As have been isolated and identified. Furthermore, the existence of PDE10 proteins has been confirmed. (Fujishige et al., J. Biol. Chem., vol. 274, pp. 18438-18445, 1999; Kotera et al., Biochem. Biophys. Res. Commun., vol. 261, pp. 551-557, 1999; Soderling et al., Proc. Natl. Acad. Sci. USA, vol. 96, pp. 7071-7076, 1999; and Loughley et al., Gene, vol. 234, pp. 109-117, 1999).
Regarding PDE10 inhibitory compounds (PDE10 inhibitors), that is, compounds having inhibitory action on the enzyme activity of PDE10, the following have been reported:
For example, in EP1250923 (Pfizer) and WO2005/082883 (Pfizer), papaverine and various aromatic heterocyclic compounds such as quinazoline and isoquinazoline compounds are disclosed as PDE10 inhibitors.
It also has been disclosed therein that PDE10 inhibitors are useful for the treatment or prophylaxis of diseases or conditions such as:
Psychotic Disorder:
for example, schizophrenia, schizophreniform disorder,
delusional disorder, schizoaffective disorder, substance-induced psychotic disorder, paranoid or schizoid personality disorder, etc;
Anxiety Disorder:
for example, panic disorder, agoraphobia, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, etc;
Movement Disorder:
for example, Huntington's disease, dyskinesia associated with dopamine agonist therapy, Parkinson's disease, restless leg syndrome, etc;
Drug Addiction:
for example, addiction to alcohol, amphetamine, cocaine, or opiate, etc;
Disorders Comprising Deficient Cognition as a Symptom:
for example, dementia (including Alzheimer's disease, multi-infarct dementia, etc), delirium, amnestic disorder, post-traumatic stress disorder, mental retardation, a learning disorder, attention deficit hyperactivity disorder (ADHD), age-related cognitive decline, etc; andMood Disorder:for example, major depressive disorder, dysthymic disorder, minor depressive disorder, bipolar disorder (including bipolar I disorder, bipolar II disorder), cyclothymic disorder, etc; orMood Episode:for example, major depressive episode, manic or mixed episode, hypomanic episode, etc.
Further, it also has been disclosed therein that PDE10 inhibitors are useful for the treatment or prophylaxis of neurodegenerative disorders, for example, Parkinson's disease, and Hungtington's disease, etc.
In the literature of Menniti et al. [Menniti et al., Curr. Opin. Investig. Drugs., 2007, 8(1):54-59], it is disclosed that PDE10 inhibitors have potential as antipsychotic agents along with potential to improve cognitive symptoms in schizophrenia.
WO2003/000693 (Bayer) discloses imidazotriazine compounds as PDE10 inhibitors. It also discloses that PDE10 inhibitors are useful for the treatment or prophylaxis of neurodegenerative disorders, especially for Parkinson's disease.
WO2003/014117 (Bayer) discloses various pyrroloisoquinoline compounds as PDE10 inhibitors. It also discloses that these compounds having inhibitory action on PDE10 activity show antiproliferative activity and are useful for treating cancer. Further, it discloses that those compounds are useful for treating conditions of pain and/or for lowering the temperature of the body in fever condition.
WO2005/12485 (Bayer) discloses that PDE10 inhibitors are useful for stimulating insulin release from pancreatic cells. Further, it is disclosed that PDE10 inhibitors are useful for the treatment or prophylaxis of diabetes and diseases related thereof:
for example, type 1 or type 2 diabetes, maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (IGT), impaired fasting glucose (IGF), gestational diabetes, metabolic syndrome X, etc.
See also WO2005/120514 (Pfizer), which discloses PDE10 inhibitors that are said to be useful to decrease body weight and/or body fat in the treatment of obese patients. Further, it is disclosed therein that those PDE10 inhibitors are useful for treatment of non-insulin dependent diabetes (NIDDM), metabolic syndrome and glucose intolerance etc.
Here, with respect to the pyrazolopyrimidine compounds, the following compounds are known.
WO2007/076055 (Entremed Inc.) discloses pyrazolopyrimidine compounds having an action as a proteinase activated receptor antagonist. However, they are clearly different from the compounds of the present invention in terms of their pharmacological action and structure.